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Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):9707-9712. doi: 10.1073/pnas.1707039114. Epub 2017 Aug 21.

Hsp90 activator Aha1 drives production of pathological tau aggregates.

Author information

1
Department of Molecular Medicine and Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613.
2
Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS 66045.
3
Department of Molecular Medicine and Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613; lblair@health.usf.edu.

Abstract

The microtubule-associated protein tau (MAPT, tau) forms neurotoxic aggregates that promote cognitive deficits in tauopathies, the most common of which is Alzheimer's disease (AD). The 90-kDa heat shock protein (Hsp90) chaperone system affects the accumulation of these toxic tau species, which can be modulated with Hsp90 inhibitors. However, many Hsp90 inhibitors are not blood-brain barrier-permeable, and several present associated toxicities. Here, we find that the cochaperone, activator of Hsp90 ATPase homolog 1 (Aha1), dramatically increased the production of aggregated tau. Treatment with an Aha1 inhibitor, KU-177, dramatically reduced the accumulation of insoluble tau. Aha1 colocalized with tau pathology in human brain tissue, and this association positively correlated with AD progression. Aha1 overexpression in the rTg4510 tau transgenic mouse model promoted insoluble and oligomeric tau accumulation leading to a physiological deficit in cognitive function. Overall, these data demonstrate that Aha1 contributes to tau fibril formation and neurotoxicity through Hsp90. This suggests that therapeutics targeting Aha1 may reduce toxic tau oligomers and slow or prevent neurodegenerative disease progression.

KEYWORDS:

Aha1; Alzheimer’s disease; Hsp90; chaperones; tau oligomers

PMID:
28827321
PMCID:
PMC5594679
DOI:
10.1073/pnas.1707039114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: C.A.D., L.B.S., B.S.J.B., J.K., and L.J.B. are the coinventors for the following provisional patent application: “The Hsp90 Activator Aha1 Drives Production of Pathological Tau Aggregates.”

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